The possibility of a major influenza pandemic (especially the avian H1N1 influenza) continues to be a serious health concern. The development of effective antiviral medicines is hampered by the exceptionally high mutation rates of influenza virus. Therefore, in order to be successful, new drugs should target the molecular mechanisms specific to the proliferation of the virus. The mechanism of infection involves the protein neuraminidase (NA), essential to viral replication. NA is responsible for the glycosidic cleavage of sialic acid (A) (in Scheme 1) from a glycoprotein of a host cell in a process that liberates the virion from the infected cell [(a) Russell, R. J.; Haire, L. F.; Stevens, D. J.; Collins, P. J.; Lin, Y. P.; Blackburn, G. M.; Hay, A. J.; Gamblin, S. J.; Skehel, J. J. Nature 2006, 443, 45; (b) Colman, P. M.; Varghese, J. N.; Layer, W. G. Nature 1983, 303, 41]. The NA protein active site appears to be conserved in many strains of the influenza A and B virus. Therefore, an efficient inhibitor of the NA protein could provide a broad-spectrum anti-influenza drug. Two compounds have been found most effective in mimicking the oxonium intermediate of sialic acid glycolysis, (i.e. structure (B) in Scheme 1), and hence acting as excellent inhibitors of NA: zanamivir (C) and oseltamivir phosphate (1a), Tamiflu® (also shown in Scheme 1). Tamiflu® appears to be superior to zanamivir because it is orally active and serves as prodrug, the active form of which is the corresponding carboxylic acid. It also has a superior bioavailability and is active at nanomolar levels. For the most recent reviews of Tamiflu® activity, supply problems, and its syntheses see: Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, ASAP web edition; (b) Farina, V.; Brown, J. D. Angew. Chem. Int. Ed. 2006, 45, 7330.
Oseltamivir is not a complex molecule yet its practical synthesis on a scale large enough to guard against an influenza pandemic presents a formidable challenge. Stockpiles of Tamiflu® and similar agents are currently the focus of many governments worldwide.

A formal chemoenzymatic synthesis of oseltamivir (1) from ethyl benzoate in ten steps compressed to just seven operations was recently reported (Sullivan, B.; Carrera, I.; Drouin, M.; Hudlicky, T. Angew. Chem. Int. Ed. 2009, 48, 4229-4231). While this particular synthesis compared very favorably with most preparations reported to date it still relied on the use of azide as means of introduction of the C-5 amino group [for the most recent reviews of approaches to oseltamivir or Tamiflu® see: (a) J. Magano Chem. Rev. 2009, 109, 4398; (b) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 11, 1839; (c) Farina, V.; Brown, J. D. Angew. Chem. Int. Ed. 2006, 45, 7330, Hudlicky, T. PCT Patent Application No. PCT/CA20009/000622, May 12, 2009]. For other syntheses of oseltamivir or Tamiflu® previously reported in the literature see: (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Layer, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681; (b) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; N.; Chen, X.; Escarpe, P. A.; Mendel, D. B.; Layer, W. G.; Stevens, R. C. J. Med. Chem. 1998, 41, 2451; (c) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545; (d) M. Federspiel, R. Fischer, M. Hennig, H.-J. Mair, T. Oberhauser, G. Rimmler, T. Albiez, J. Bruhin, H. Estermann, C. Gandert, V. Göckel, S. Götzö, U. Hoffmann, G. Huber, G. Janatsch, S. Lauper, O. Röckel-Stäbler, R. Trussardi, A. G. Zwahlen Org. Process Res. Dev. 1999, 3, 266; (e) Karpf, M.; Trussardi, R. J. Org. Chem., 2001, 66, 2044; (f) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Proc. Res. Dev., 2004, 8, 86; (g) Sungwoo Hong, Y.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310; (h) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312.; (i) Cong, X.; Yao, J.-Z. J. Org. Chem. 2006, 71, 5365; (j) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong, C.-H. J. Am. Chem. Soc. 2007, 129, 11892; (k) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem. Int. Ed. 2007, 46, 5734; (l) Bromfield, K. M.; Gradén, H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem. Commun. 2007, 3183; (m) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259; (n) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 1403; (o) Matveenko, M.; Willis, A. C.; Banwell, M. G. Tetrahedron Lett. 2008, 49, 7018; (p) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew. Chem. Int. Ed. 2008, 47, 5788; (q) Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10, 815; (r) Trost, B. M.; Zhang, T. Angew. Chem. Int. Ed. 2008, 120, 3819; (s) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73, 4895; (t) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem. Int. Ed. 2009, 48, 1304; (u) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew. Chem. Int. Ed. 2009, 48, 1070; (v) Oshitari, T.; Mandai, T. Synlett 2009, 787; (w) Carbain, B.; Martin, S. R; Collins, P. J.; Hitchcock, P. B.; Streicher, H. Org. Biomol. Chem., 2009, 7, 257; (x) Yamatsugu, K.; Kanai, M; Shibasaki, M. Tetrahedron 2009, 65, 601; (y) Resende, R.; Glover C.; Watts, A. G. Tetrahedron Lett. 2009, 50, 4009. For previously reported commercial syntheses see: (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, S.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Layer, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681; (b) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545; (c) M. Federspiel, R. Fischer, M. Hennig, H.-J. Mair, T. Oberhauser, G. Rimmler, T. Albiez, J. Bruhin, H. Estermann, C. Gandert, V. Göckel, S. Götzö, U. Hoffmann, G. Huber, G. Janatsch, S. Lauper, O. Röckel-Stäbler, R. Trussardi, A. G. Zwahlen Org. Process Res. Dev. 1999, 3, 266; (d) Abrecht, S.; Federspiel, M. C.; Estermann, H.; Fischer, R.; Karpf, M.; Mair, H.-J.; Oberhauser, T.; Rimmler, G.; Trussardi, R.; Zutter, U. Chimia 2007, 61, 93].